Vedolizumab use and the associations between α4β7 expression and HIV reservoir in the gut during treated primary HIV infection

A cure for HIV infection remains elusive with two cases of HIV cure to date [1,2], both resulting from haematopoietic stem-cell transplantation (HSCT). Whilst interesting as proof of concept, HSCT is associated with high morbidity and mortality and is not scalable; therefore, alternative strategies towards a HIV cure are being explored. Antiretroviral therapy (ART) confers a significant survival benefit but cannot cure HIV infection – a consequence of latently infected CD4+ T cells, particularly, within tissue sites. Gut-associated lymphoid tissue (GALT) serves as one of the main barriers to HIV eradication [3]. α4β7 integrin is a gut homing marker expressed on CD4+ T cells, which allows trafficking of CD4+ T cells to gut tissue [4]. Furthermore, HIV preferentially infects α4β7+CD4+ T cells [5]. Antibodies targeting α4β7 are used to treat inflammatory bowel disease [6]. In simian immunodeficiency virus (SIV)-infected primates, initial reports suggested treatment with a mononclonal antibody against α4β7 integrin and ART conferred viral control after stopping ART following administration in early infection [7]. We characterized β7 expression and total HIV DNA levels from gut lamina propria mononuclear cells (LPMC) in HEATHER: a UK multicenter prospective cohort of patients with a primary HIV infection (PHI) who commenced on ART within 3 months of PHI diagnosis [8]. In addition, we present the case of an individual from the HEATHER cohort, with ART-treated PHI who also received treatment with a licensed anti-α4β7 integrin monoclonal antibody, vedolizumab, for Crohn's disease. Matched peripheral blood mononuclear cell (PBMC) and gut LPMC isolated from the terminal ileum and rectum from 24 individuals in HEATHER were available. β7 expression – the proportion of memory (CD45RA-CD4+) T cells, which were β7-positive – was determined by a fluorescence minus one control using flow cytometry. Total HIV DNA was quantified from collagenase digested LPMCs by qPCR. One of the 24 individuals was diagnosed with Crohn's disease 5 months prior to HIV acquisition (Fig. 1a). This 31-year-old MSM tested negative for HIV at his Crohn's diagnosis and again 2 months later. His Crohn's disease was initially managed with prednisolone induction and subsequent azathioprine maintenance. Eight months following the diagnosis of Crohn's disease, he was diagnosed with PHI (with a CD4+ T-cell count of 475 cells/μl and a HIV viral load of 44 038 copies/ml). ART was commenced 28 days after PHI diagnosis with Truvada and raltegravir. Raltegravir was switched to darunavir and ritonavir 1 month later based on HIV genotype testing. HIV viral load was less than 20 copies RNA/ml within 5 months of ART initiation. Twelve months after the diagnosis of Crohn's disease and 3 months after PHI, colonoscopy confirmed active ileitis and vedolizumab was commenced. Follow-up biopsy, 4 months after commencing vedolizumab, showed gross resolution of ileal inflammation with only mild residual chronic active granulomatous colitis on histopathology. Research gut biopsies were taken at this timepoint.Fig. 1: The clinical course of the HEATHER participant who received vedolizumab in primary HIV infection is shown in (a).The correlation of the expression of β7 on memory CD4+ T cells and total HIV DNA from individuals in the HEATHER cohort from the (b) terminal ileal and (c) rectal GALT is shown. (d) The β7 expression on memory CD4+ T cells across anatomical sites for the HEATHER cohort is shown; data from the individual who received vedolizumab treatment indicated by the solid shapes is shown. (e) The total HIV DNA measured from CD4+ T cells across anatomical sites for the HEATHER cohort is shown; again, data from the individual who received vedolizumab treatment is indicated by the solid shapes.β7 expression on memory CD3+CD4+ LPMCs from the overall HEATHER cohort (n = 24) correlated with total HIV DNA in the terminal ileum (r = 0.67; P = 0.0007; Fig. 1b) and rectum (r = 0.46; P = 0.03; Fig. 1c). The vedolizumab-treated individual had the lowest β7 expression on CD3+CD4+ LPMCs measured in the terminal ileum (5.2%) and relatively lower expression in the rectum (8.1%) when compared with other HEATHER participants, as well as the highest measured β7 expression on PBMC-derived memory CD4+ T cells (24%). Median β7 expression for the HEATHER cohort was 27.1%, 18.3%, and 11% in the terminal ileum, rectum and PBMC, respectively (Fig. 1d). Correspondingly, HIV DNA levels in gut LPMCs for the vedolizumab-treated participant were at or just below the median, whereas his PBMC HIV DNA was the highest measured in the overall cohort (Fig. 1e). To confirm the presence of replication-competent viral reservoirs in this patient, PBMCs obtained from the vedolizumab-treated participant were subsequently analysed by humanized murine viral outgrowth assay [9]. For this, two timepoints after vedolizumab treatment were evaluated and resulted in detectable serum HIV RNA in mice at days 14 and 28. Together, these results suggest that vedolizumab reduced trafficking of β7 expressing CD4+ T cells to the gut and support recent work from Uzzan et al. who reported significant attenuation of lymphoid aggregates, most notably in the terminal ileum with anti-α4β7 therapy [10]. These data also demonstrate an association between β7 expression and HIV DNA measured in gut LPMCs. Despite this, and consistent with other work in humanized mice [11] and the first unpublished human study using vedolizumab in HIV+ individuals [12]; our data suggests that whereas vedoluzimab treatment may confer lower expression of β7 on CD4+ T cells in gut LPMCs, vedoluzimab is unlikely to induce sustained viral remission. Acknowledgements We thank the participants of HEATHER. The HEATHER study is conducted as part of the CHERUB (Collaborative HIV Eradication of Reservoirs: UK BRC) collaboration. CHERUB Steering Committee: Andrew Lever (University of Cambridge), Mark Wills (University of Cambridge), Jonathan Weber (Imperial College, London), Sarah Fidler (Imperial College, London), John Frater (University of Oxford), Lucy Dorrell (University of Oxford), Mike Malim (King's College, London), Julie Fox (King's College London), Ravi Gupta (University College London), Clare Jolly (University College London). Authors’ contributions: The study experiments were conceived and designed by J.T., K.L., G.M., J.H., S.P., J.F. and S.F. Recruitment of the trial samples were performed by J.T., J.F., S.P., J.H. and S.F. Gut biopsy processing, HIV DNA quantification and flow cytometry experiments were performed by J.T., K.L. and M.K. The humanized mouse model experiment was performed by J.S. and M.D. Data was analysed by J.T., J.S. and M.D. The article was written by J.T. with input from all authors. Funding: This work was supported by Medical Research Council Fellowship (grant MR/N001265/1 to J.T.) and a British HIV Association Research Award (to J.T.). Conflicts of interest There are no conflicts of interest.

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